Hepatic encephalopathy is defined as a spectrum of neuropsychiatric abnormalities in patients with liver failure, after exclusion of other known brain disease. Hepatic encephalopathy can be subdivided into covert hepatic encephalopathy and overt hepatic encephalopathy.
Covert hepatic encephalopathy is a subclinical, less severe manifestation of hepatic encephalopathy and requires psychometric testing for diagnosis.Covert hepatic encephalopathy has a significant impact on a patient's quality of life, including employment and driving performance, and is associated with increased admissions to hospital and with death.
Features of hepatic encephalopathy include personality changes, intellectual impairment and reduced levels of consciousness. The pathogenesis of hepatic encephalopathy is uncertain but may be due to the passage of neurotoxins to the brain.Hepatic encephalopathy develops in up to 50% of patients with cirrhosis and is a feature of decompensated cirrhosis.
- Acute kidney injury.
- Electrolyte imbalance.
- Gastrointestinal bleeding.
- Sedative drugs - eg, opiates, benzodiazepines, antidepressants and antipsychotic drugs.
- High protein intake.
Grading of hepatic encephalopathy
- Grade 0: subclinical; normal mental status but minimal changes in memory, concentration, intellectual function, co-ordination. This is also termed minimal hepatic encephalopathy.
- Grade 1: mild confusion, euphoria or depression, decreased attention, slowing of ability to perform mental tasks, irritability, disorder of sleep pattern such as inverted sleep cycle.
- Grade 2: drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behaviour, intermittent disorientation.
- Grade 3: somnolent but rousable, unable to perform mental tasks, disorientation to time and place, marked confusion, amnesia, occasional fits of rage, speech present but incomprehensible.
- Grade 4: coma, with or without response to painful stimuli.
- Patients with very mild hepatic encephalopathy may have normal memory, language and motor skills but may have impairment of attention and decision-making and may have impaired fitness to drive. These patients usually have normal function on standard mental state testing but abnormal psychometric testing.
- Patients with mild and moderate hepatic encephalopathy show decreased short-term memory and concentration with testing of mental state. They may also have a flapping tremor (asterixis), fetor hepaticus (a sweet musty aroma of the breath), hyperventilation and hypothermia.
- Psychometric tests - this are becoming increasingly useful in the the diagnosis of minimal hepatic encephalopathy.
- Arterial or serum ammonia levels are raised and can help with diagnosis.
- Electroencephalogram (EEG): may show high-amplitude low-frequency waves and triphasic waves but these findings are not specific for hepatic encephalopathy, although recent work suggests EEG may be useful prognostically.
- MRI/CT scanning can help to exclude other causes of altered mental function such as intracranial lesions.
- Visual evoked responses show classic patterns associated with hepatic encephalopathy.
Other causes of encephalopathy, including:
- Intracranial lesions - eg, haemorrhage, cerebrovascular event, tumour.
- Infection - eg, meningitis, encephalitis, intracranial abscess.
- Metabolic - eg, hypoglycaemia, electrolyte imbalance, anoxia, acute kidney injury.
- Other causes of hyperammonaemia - eg, ureterosigmoidostomy, inherited urea cycle disorders.
- Toxic - eg, substance abuse, alcohol-related problems.
- Drugs - eg, sedative hypnotics, antidepressants, antipsychotic agents and salicylates.
- Early diagnosis and aggressive identification and management of precipitating factors.
- Avoidance of sedative drugs.
Restriction of protein intake was not found to be beneficial in one trial. Adequate nutrition is essential and restricting protein intake may cause or aggravate malnutrition.
- The nitrogen load from the gut should be reduced using lactulose or bowel enemas. However, a systematic review found that there is insufficient evidence to support or refute the use of non-absorbable disaccharides for hepatic encephalopathy.
- Neomycin may also be used to lower amino acid production by decreasing the concentration of ammonia-forming colonic bacteria.[9, 11]
- Other antibiotics have also been used - eg, metronidazole, vancomycin and the quinolones.
- Rifaximin is an antibiotic licensed for the treatment of traveller's diarrhoea in the USA. It is based on rifamycin and has little, if any, systemic absorption. It has been shown to be beneficial in patients with minimal hepatic encephalopathy.
- Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor complex in the brain, resulting in neural inhibition. Flumazenil (a benzodiazepine antagonist) has been shown to have a significant, beneficial effect on short-term improvement of hepatic encephalopathy in patients with cirrhosis, but with no significant effect on recovery or survival.
- Hepatic encephalopathy may be associated with an impairment of dopaminergic neurotransmission. However, there is insufficient evidence that dopamine agonists are of benefit to patients with acute or chronic hepatic encephalopathy, or fulminant hepatic failure.
- Hepatic encephalopathy may be caused by a decreased plasma ratio of branched-chain amino acids to aromatic amino acids. A Cochrane review found that branched-chain amino acids had a beneficial effect on hepatic encephalopathy but did not find any effect on mortality, quality of life, or nutritional parameters.
The prognosis is dependent on the degree of liver failure, comorbidities and the timing of effective treatment, especially of precipitating factors. The development of hepatic encephalopathy in patients with cirrhosis is associated with a worse prognosis and may lead to frequent and severe relapses. Patients with overt hepatic encephalopathy in hospital have a 3.9-fold increased mortality risk.
Rifaximin is recommended by the National Institute for Health and Care Excellence (NICE) as an option for reducing the recurrence of episodes of overt hepatic encephalopathy in people aged 18 years or older.
Further reading and references
Liu A, Perumpail RB, Kumari R, et al; Advances in cirrhosis: Optimizing the management of hepatic encephalopathy. World J Hepatol. 2015 Dec 187(29):2871-9. doi: 10.4254/wjh.v7.i29.2871.
Patidar KR, Bajaj JS; Covert and Overt Hepatic Encephalopathy: Diagnosis and Management. Clin Gastroenterol Hepatol. 2015 Nov13(12):2048-61. doi: 10.1016/j.cgh.2015.06.039. Epub 2015 Jul 9.
Grover VP, Tognarelli JM, Massie N, et al; The why and wherefore of hepatic encephalopathy. Int J Gen Med. 2015 Dec 168:381-90. doi: 10.2147/IJGM.S86854. eCollection 2015.
Leise MD, Poterucha JJ, Kamath PS, et al; Management of hepatic encephalopathy in the hospital. Mayo Clin Proc. 2014 Feb89(2):241-53. doi: 10.1016/j.mayocp.2013.11.009. Epub 2014 Jan 8.
Mullen KD; Review of the final report of the 1998 Working Party on definition, nomenclature and diagnosis of hepatic encephalopathy. Aliment Pharmacol Ther. 2007 Feb25 Suppl 1:11-6.
Marchetti P, D'Avanzo C, Orsato R, et al; Electroencephalography in patients with cirrhosis. Gastroenterology. 2011 Nov141(5):1680-1689.e2. Epub 2011 Jul 18.
Shawcross D, Jalan R; Dispelling myths in the treatment of hepatic encephalopathy. Lancet. 2005 Jan 29-Feb 4365(9457):431-3.
Cordoba J, Lopez-Hellin J, Planas M, et al; Normal protein diet for episodic hepatic encephalopathy: results of a randomized study. J Hepatol. 2004 Jul41(1):38-43.
Heidelbaugh JJ, Sherbondy M; Cirrhosis and chronic liver failure: part II. Complications and treatment. Am Fam Physician. 2006 Sep 174(5):767-76.
Als-Nielsen B, Gluud LL, Gluud C; Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomised trials. BMJ. 2004 May 1328(7447):1046. Epub 2004 Mar 30.
Schuppan D, Afdhal NH; Liver cirrhosis. Lancet. 2008 Mar 8371(9615):838-51.
Bajaj JS, Heuman DM, Wade JB, et al; Rifaximin improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy. Gastroenterology. 2011 Feb140(2):478-487.e1. Epub 2010 Sep 21.
Als-Nielsen B, Gluud LL, Gluud C; Benzodiazepine receptor antagonists for hepatic encephalopathy. Cochrane Database Syst Rev. 2004(2):CD002798.
Junker AE, Als-Nielsen B, Gluud C, et al; Dopamine agents for hepatic encephalopathy. Cochrane Database Syst Rev. 2014 Feb 102:CD003047. doi: 10.1002/14651858.CD003047.pub3.
Gluud LL, Dam G, Les I, et al; Branched-chain amino acids for people with hepatic encephalopathy. Cochrane Database Syst Rev. 2015 Feb 252:CD001939. doi: 10.1002/14651858.CD001939.pub2.
Chacko KR, Sigal SH; Update on management of patients with overt hepatic encephalopathy. Hosp Pract (1995). 2013 Aug41(3):48-59. doi: 10.3810/hp.2013.08.1068.
Rifaximin for preventing episodes of overt hepatic encephalopathy; NICE Technology Appraisal Guidance, March 2015